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Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P < 0.001). The enhanced efficacy of IL-15/IL-15Rα-NKG2D CAR T cells was probably due to the IL-15/IL-15Rα signaling improved homing and persistence of NKG2D CAR-T cells in vivo, and increased the production of IFN-γ, Perforin, and Granulysin. In conclusion, NKG2D CAR-T cells co-expressing IL-15/IL-15Rα promoted the central memory CAR T cell proliferation and improved the homing and persistence of CAR T cells in vivo, resulting in enhanced anti-tumor and anti-viral effects in treating EBV-PTLD.

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Bilateral adrenal hemorrhage (AH) is linked to various causes, including bacterial and viral infections, coagulopathies, and postoperative states. Symptoms can range from mild adrenal insufficiency to shock from Waterhouse-Friedrichsen syndrome. We present a case of a 47-year-old male with antiphospholipid antibody syndrome (APS) on warfarin who presented to the emergency department (ED) with bilateral flank pain and was found to have bilateral AH. On exam, he was hypertensive, mildly tachycardic, and in severe pain. The abdomen was tender over the bilateral flank and costovertebral regions. Labs showed thrombocytopenia but normal international normalized ratio (INR) and fibrinogen. The CT and MRI confirmed bilateral AH. Further investigations revealed low ante meridiem (AM) cortisol and elevated adrenocorticotropic hormone (ACTH). The antinuclear antibody (ANA) test was negative, but the antiphospholipid antibody panel was positive. In addition, the patient had a positive Epstein-Barr virus (EBV) nuclear antigen with a significant IgM titer. He was treated with low-dose steroids and was placed on a prophylactic dose of enoxaparin with the resolution of symptoms. At discharge, he was advised to follow up with a hematologist in six weeks to restart full-dose anticoagulation, allowing time for the bleeding to resolve. This case highlights EBV infection as a possible trigger of adrenal insufficiency from adrenal bleeding in a patient with preexisting coagulopathy, necessitating prompt recognition and treatment.

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OBJECTIVE: To analyze the risk factors of Epstein-Barr virus (EBV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its impact on survival. METHODS: The clinical data of 347 patients who underwent their first allo-HSCT in our hospital from January 2014 to June 2021 were retrospectively analyzed. Patients were divided into EBV (n =114) and Non-EBV (n =233) groups according to whether they were infected with EBV. The incidence of EBV infection after allo-HSCT was calculated, and the risk factors of EBV infection were analyzed. RESULTS: A total of 114(32.8%) patients presented EBV infection (all peripheral blood EBV-DNA were positive). EBV infection occurred in 88 patients within 100 days after transplantation, which accounted for 77.2% of all patients with EBV infection. 5 cases (1.44%) were confirmed as post-transplant lymphoproliferative disorder (PTLD). The median onset time of patients was 57(7-486) days after transplantation. Multivariate analysis showed that the use of ATG/ATG-F, occurrence of CMV viremia, and grade III-IV aGVHD were risk factors for EBV infection. Furthermore, compared to BUCY, the use of intensified preconditioning regimens containing FA/CA was significantly increased the risk of EBV infection. CONCLUSION: EBV infection is a common complication after allo-HSCT. Intensified preconditioning regimens, use of ATG/ATG-F, CMV viremia and grade III to IV aGVHD increase the risk of EBV infection after allo-HSCT.

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Background: Children undergoing allo-HCT are at high risk of EBV-related complications. The objective of the study was to analyze the impact of prophylactic post-transplant rituximab on EBV infection and EBV-PTLD in children after allo-HCT, to determine the risk factors for the development of EBV infection and EBV-PTLD and to determine their outcomes. Additionally, the impact of EBV-driven complications on transplant outcomes was analyzed. Methods: Single center retrospective analysis of EBV-related complications in pediatric population undergoing allo-HCT, based on strategy of prophylaxis with rituximab. Overall 276 consecutive children, including 122 on prophylaxis, were analyzed for EBV-driven complications and transplant outcomes. Results: Prophylaxis with rituximab resulted in significant reduction of EBV infection (from 35.1% to 20.5%; HR=2.7; p<0.0001), and EBV-PTLD (from 13.0% to 3.3%; HR=0.23; p=0.0045). A trend for improved survival was also observed (HR=0.66; p=0.068), while non-relapse mortality was comparable in both cohorts. The peak value of viral load was a risk factor in the development of EBV-PTLD: 10-fold higher peak viral load in comparison to the baseline 104 copies/mL, caused a 3-fold (HR=3.36; p<0.001) increase in the risk of EBV-PTLD. Rituximab treatment was effective as a preemptive therapy in 91.1%, and in 70.9% in EBV-PTLD. Patients who developed PTLD had dismal 5-year overall survival (29% vs 60%; p<0.001), and an increased risk of relapse (72% vs 35%; p=0.024). Conclusions: Rituximab for prophylaxis of EBV infection and EBV-PTLD was highly effective in pediatric population. Treatment of EBV-PTLD was successful in 70%, however the occurrence of EBV-PTLD was associated with an increased risk of relapse of primary malignant disease.

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PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

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OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.

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Background: Junctional epithelium (JE) provides the front-line defense against pathogens invading periodontium. The breakdown of the JE barrier is the hallmark of periodontitis. Recent studies have implicated the Epstein-Barr virus (EBV) as one of the etiopathogenetic factors of periodontitis. EBV exhibits tropism for two target cells in vivo: B cells, where it primarily remains latent, and epithelial cells, where viral replication occurs. Objective: Our knowledge of junctional epithelial cell (JEC) infection with EBV has been limited by the difficulty of generating cell cultures and the inability to infect JECs in vitro readily. Design: To study EBV infection in JECs, we developed human JEC cultures derived from a periodontitis patient. Furthermore, we established a successful contact-free co-culture infection model between the EBV-donor B95-8 cell line and the EBV-permissive JEC culture. JECs and EBV infection of JECs were detected using immunofluorescent staining of cytokeratin 19 and EBNA1, respectively. In addition, EBV infection was confirmed by RT-qPCR for EBNA1, LMP1, and BZLF1 expression. Results and conclusions: Our results suggest that the infection of JECs with EBV can occur in an in vitro experimental model. These outcomes have the potential to enhance our understanding of EBV's involvement in periodontitis and advance periodontal research.

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Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms and is associated with EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders, which frequently lead to the development of life-threatening complications, such as virus-associated hemophagocytic syndrome and EBV-positive apparent leukemia/lymphoma mainly in T- and NK-cell lineages. In order to clarify the EBV genes responsible for the diseases, we introduced the plasmid coding sequences of EBV-encoded small RNAs (EBERs) and/or latent membrane protein (LMP) 1 into human T-lymphocyte virus-I-negative human T-cell lines using a gene expression vector harboring EBV nuclear antigen 1, established the G418-resistant transformants of five T-cell lines, and quantitatively examined the expression of EBERs and LMP1 using real-time reverse transcriptase-polymerase chain reaction. The expression levels of EBERs in T-cell transformants with EBER DNA paralleled those in EBV-positive human T- and NK-cell lines, SNTK cells. The expression of LMP1 mRNA varied in SNTK cells and in human T-cell transformants, and the expression of LMP1 mRNA in T-cell lines expressing both EBERs and LMP1 was much lower than that in the same cell line expressing LMP1 mRNA alone. The currently employed gene expression system and currently obtained transformants may be useful for the analyses of the pathophysiology of CAEBV and EBV-positive T/NK-cell lymphoproliferative disorders.

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OBJECTIVE: The aim: To investigate the clinical characteristics of EBV infection in the pediatric nervous system using laboratory methods and brain MRI data. PATIENTS AND METHODS: Materials and methods: We observed 41 children with EBV encephalitis ranging from 8 months to 17 years old. The diagnosis of EBV-encephalitis was established on the basis of clinical and medical history, laboratory and instrumental (brain MRI) data. The main thing in the diagnosis was clinical symptoms, combining general infection, cerebral syndromes and focal neurological symptoms. The etiology of Epstein-Barr virus was determined using ELISA and PCR. RESULTS: Results: EBV-encephalitis can be as a manifestation of reactivation of persistent EBV infection (85%), much less often - acute primary EBV infection (15%). By nature, the duration of EBV encephalitis has distinguished two forms of its course: acute (63%) and chronioc (37%). The criteria of differential diagnosis of acute and chronic forms of EBV-encephalitis are proposed, which include the most common anamnesis data, clinical manifestations and changes in brain MRI. CONCLUSION: Conclusions: The proposed criteria specifically for acute and chronic forms of EBV-encephalitis can contribute to the timely and more accurate diagnosis of this disease in children.

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Aim of the study: To assess the expression of selected miRNAs as predictive factors of hepatological complications in Epstein-Barr virus (EBV)-infected children. Material and methods: This study included 68 children infected with EBV aged 1 to 18 years hospitalised between 01.12.2018 and 31.12.2020 in the Department of Paediatrics, Infectious Diseases and Hepatology. The expression of 5 miRNAs (miR-122-5p, miR-21-3p, miR-34a-5p, miR-26b-5p, miR-199a-5p) was analysed by real-time PCR using the TaqMan Fast Advanced Master Mix kit. Results: In the group of EBV-infected children, statistically significantly higher expression for miR-21-3p, miR-122-5p, miR-26b-5p and miR-34a-5p was confirmed. In a group of 54 children diagnosed with hepatitis, along with an increase in alanine aminotransferase (ALT) and g-glutamyl transpeptidase (GGTP) activity, an increase in expression of miR-21-3p, miR-122-5p, miR-26b-5p, miR-34a-5p and miR-199a-5p was observed. Conclusions: Increased expression of miR-21-3p, miR-122-5p, miR-26b-5p, miR-34a-5p and miR-199a-5p in EBV-infected children appears to be a risk factor for hepatological complications progressing to biliary pole defects.

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The relationship between Toll-like receptor 9 (TLR-9) signaling and its involvement with Epstein-Barr virus (EBV) in gastric cancer (GC) is complex and currently under study. This research intended to understand TLR-9's role in certain T and B lymphocytes and the serum levels of TLR-9 in GC patients versus healthy subjects. The team explored links between these immune markers and various GC traits, such as histological grade, tumor progression stages, cancer types, and survival rates. Additionally, the research sought to find if EBV genetic material influences these immune reactions. Using flow cytometry, TLR-9 levels in different immune cells were analyzed. At the same time, the amount of TLR-9 in the serum was determined. The results showed GC patients had varied TLR-9 levels compared to healthy subjects, with specific cells showing noticeable changes. When grouped by GC attributes, key relationships emerged between TLR-9 amounts, the histological grade, progression stages, and cancer types. A notable finding was the connection between TLR-9 levels and EBV genetic presence, suggesting possible interactions between TLR-9 responses and EBV-related GC processes. Survival data also hinted at TLR-9's potential as a predictor linked to clinical traits. Overall, this research emphasizes TLR-9's complex role in GC's immune responses, pinpointing its interactions with particular cells, clinical features, and EBV. The study unveils a complex web affecting GC and paves the way for new treatment avenues targeting TLR-9 pathways.

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The aim of the study was to evaluate tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), soluble intracellular adhesion molecules 1 (s-ICAM-1) and Epstein-Barr virus (EBV) DNA load levels as predictors of hepatological complications of EBV infection in children. The study group consisted of 54 children aged one to eighteen years, who were hospitalised from 1 December 2018 to 31 December 2020 in the Department of Paediatrics, Infectious Diseases and Hepatology and who had hepatological complications in the course of serologically and molecularly confirmed EBV infection. It was shown that IL-6, TNF-α, and s-ICAM-1 concentrations were the highest in patients with hepatitis and biliary pole damage. Higher EBV DNA viremia positively correlated with increased C-reactive protein (CRP) and TNF-α levels and increased leukocyte, lymphocyte, and monocyte counts. Increases in lymphocyte counts and TNF-α concentrations were observed along with increases in gamma-glutamyl transpeptidase (GGTP) activity. Increased concentrations of IL-6, TNF-α, and s-ICAM-1 may indicate the risk of hepatitis with concomitant biliary pole damage during EBV infection.

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BACKGROUND: Quantitative polymerase chain reaction (qPCR) for Epstein-Barr virus (EBV)-DNA is an important diagnostic tool for EBV-associated disease, but interpretation of its clinical significance is challenging. OBJECTIVES: We assessed the diagnostic and clinical performance of WHO-standardised qPCR for EBV-DNA (WHO EBV-qPCR) in plasma and whole blood (WB) for proven EBV disease in a prospectively accrued patient cohort. STUDY DESIGN: Central Denmark Region patients, tested with WHO EBV-qPCR from November 2017 to March 2019, were screened for EBV disease. Incidence (IR) was estimated by Poisson regression. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were calculated for EBV-qPCR in plasma and WB. Risk of diagnostic latency was compared between patients with EBV-positive and EBV-negative lymphomas. RESULTS: EBV disease was diagnosed in 95 of 1484 participants (IR: 16.3 per 1000 patientyears 95%CI; 13.3-19.9). Sensitivity and specificity of WHO EBV-qPCR in plasma was 82.4% (95% CI; 74.2-90.7%) and 87.8% (95% CI; 85.6-90%), yielding a PPV of 32.2% (95% CI; 24.9-39.5%) and NPV of 98.6% (95% CI; 97.7-99.5%) for proven EBV disease. Sensitivity and NPV were comparable in WB, while specificity and PPV decreased to 66.9% (95% CI; 60.6-73.1%) and 18.1% (95% CI; 7.5-28.7%). Risk of diagnostic latency was 2.3-fold (95% CI 1.4-4.1) higher for patients with EBV-positive compared with EBV-negative lymphomas. CONCLUSIONS: WHO EBV-qPCR in plasma and WB have a low PPV but a high NPV for proven EBV disease. Implementation of WHO EBV-qPCR could improve interpretation and facilitate EBV-positive lymphoma diagnosis.

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PURPOSE: To characterize the magnetic resonance imaging features of primary intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC). MATERIALS AND METHODS: Thirty-four patients with 38 histologically confirmed LELCCs were enrolled retrospectively from January 2014 to August 2022. We evaluated the clinical features, histologic findings, and imaging manifestations on dynamic enhanced MRI. RESULTS: 74% (25/34) of the cases were associated with EBV infection. Moreover, patients infected with EBV exhibited a lower level of Ki-67 proliferation. The serum CA199 level was elevated in 10 patients. The median tumor diameter was 2.8 cm (range, 1.1-8.7 cm). Most tumors were well-defined with a smooth or lobulated margin and showed peripheral hyperintensity and central hypointensity on T2-weighted imaging (T2WI). T2 hyperintense foci were recognized in 8 patients. In the dynamic enhanced MRI, 21 tumors demonstrated Type A enhancement pattern (rim enhancement), 10 demonstrated Type B (rapid wash-in and wash-out), and seven demonstrated Type C (rapid wash-in without wash-out). Capsular enhancement in PVP or DP was found in 22 tumors. A few patients had satellite lesions, portal vein thrombosis, bile duct dilatation, and distal metastasis. Lymph node metastases were discovered pathologically in 11 patients. CONCLUSIONS: MRI findings of LELCC vary and are non-specific. While a majority of LELCCs exhibit typical features of intrahepatic cholangiocarcinoma (iCCA), unique findings like T2 hyperintense foci or capsular enhancement could suggest LELCC. EBV infection and elevated tumor markers can aid in differentiation. However, given the mimics of some cases of liver hypervascular lesions, histological examination remains essential for definitive diagnosis.

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Objectives: Epstein-Barr virus (EBV) is a common cause of secondary haemophagocytic lymphohistiocytosis (HLH). While B cells are reservoirs for EBV, infection within T cells and NK cells in this disease can be difficult to treat. Methods: A 19-year-old female presented with a 6-week history of coryzal symptoms on a background of Crohn's disease. On examination, she was febrile and tachycardic with mild tonsillar enlargement and splenomegaly. New trilineage cytopenias and elevation in liver enzymes were detected, with acute EBV subsequently confirmed on whole blood PCR. A diagnosis of EBV-associated HLH was supported further with elevated serum ferritin, triglycerides and soluble CD25, low fibrinogen and the presence of haemophagocytosis in the bone marrow. Results: Corticosteroids, IVIG and rituximab were given, and anakinra was subsequently added due to ongoing fevers. EBV infection was then demonstrated within CD8+ T cells on EBER Flow-FISH assay. Ruxolitinib was commenced and her fevers abated on day 5, with improvement in other HLH parameters. She was discharged after a 39-day hospital admission. To date, she has remained in remission of HLH, despite developing COVID-19 infection during the convalescence phase of HLH. Conclusion: EBV viraemia requires adequate treatment to control EBV-associated HLH as rituximab may be insufficient, and corticosteroid resistance can result in continued EBV infection in CD8+ T cells. This entity is known as T-cell-EBV-HLH. Ruxolitinib is a novel treatment strategy in this specific context and has several advantages, including inhibition of corticosteroid resistance to promote apoptosis of EBV-infected T cells.

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Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that arises due to a dysregulated immune response caused by the aberrant activation of lymphocytes and macrophages. In this rare case report, we describe a newly diagnosed human immunodeficiency virus (HIV) patient who was found to have Epstein-Barr virus (EBV) provoked HLH and co-existing Hodgkin lymphoma (HL).  Our patient was a 28-year-old newly diagnosed HIV patient who presented with nonspecific symptoms, including bilateral foot pain and tingling sensation. Laboratory findings were significant for pancytopenia. With a high index of suspicion, the patient had a bone marrow biopsy done which confirmed a diagnosis of both HLH and Hodgkin's lymphoma. The case highlighted the diagnostic dilemma of HLH in the setting of HIV infection. Identifying the major components of his disease process was pivotal to ensure that the patient was commenced on appropriate therapy for the EBV-driven HLH and HL.  The diagnosis of HLH in newly diagnosed HIV remains challenging due to the diverse clinical presentations and the need to exclude other possible causes. The clinical features of HLH, HL, and HIV can be nonspecific and overlap, creating a diagnostic dilemma. Diagnosis requires a combination of clinical, laboratory, and histopathological features. The management in such cases requires prompt diagnosis through a multidisciplinary approach, a variety of chemotherapy, immunosuppression, supportive care, and treatment of the underlying triggers.

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Infection-associated hemophagocytosis is a diagnostic challenge. The varied presentation makes timely diagnosis difficult. We report two cases with unusual presentation of well-established secondary triggers for hemophagocytic lymphohistiocytosis.

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Objectives: Increasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV-associated lymphoproliferative disease (EBV+ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8+ T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified. Methods: Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1->AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV+ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed. Results: Biallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8+ T cells from the patient had impaired activation, reduced expression/release of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV+ LPD. Conclusion: Our study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.

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Epstein-Barr virus (EBV) infection is extremely common worldwide, with approximately 90% of adults testing positive for EBV antibodies. Human are susceptible to EBV infection, and primary EBV infection typically occurs early in life. EBV infection can cause infectious mononucleosis (IM) as well as some severe non-neoplastic diseases, such as chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which can have a heavy disease burden. After primary EBV infection, individuals develop robust EBV-specific T cell immune responses, with EBV-specific CD8+ and part of CD4+ T cells functioning as cytotoxic T cells, defending against virus. Different proteins expressed during EBV's lytic replication and latent proliferation can cause varying degrees of cellular immune responses. Strong T cell immunity plays a key role in controlling infection by decreasing viral load and eliminating infected cells. However, the virus persists as latent infection in EBV healthy carriers even with robust T cell immune response. When reactivated, it undergoes lytic replication and then transmits virions to a new host. Currently, the relationship between the pathogenesis of lymphoproliferative diseases and the adaptive immune system is still not fully clarified and needs to be explored in the future. Investigating the T cell immune responses evoked by EBV and utilizing this knowledge to design promising prophylactic vaccines are urgent issues for future research due to the importance of T cell immunity.

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Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

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